Anileridine (Leritine) synthesis

[G.Patton]

Introduction​

Anileridine (trade name: Leritine) is a synthetic analgesic drug and is a member of the piperidine class of analgesic agents. It differs from pethidine (meperidine) in that the N-methyl group of meperidine is replaced by an N-aminophenethyl group, which increases its analgesic activity.

Anileridine is no longer manufactured in the US or Canada. Anileridine is in Schedule II of the Controlled Substances Act 1970 of the United States as ACSCN 9020 with a zero aggregate manufacturing quota as of 2014. The free base conversion ratio for salts includes 0.83 for the dihydrochloride and 0.73 for the phosphate. It is also under international control per UN treaties.

Containing two amino in the molecule of the raw materials used p-aminophenyl ethamine (6) of the present invention, all with sulphonate (5), ring-closure reaction occurs, to be shown below, reaction product comprises: the target product (7) that the alkylamine on p-aminophenyl ethamine (6) and sulphonate (5) react; The by product (8) that aromatic amine on p-aminophenyl ethamine (6) and sulphonate (5) react; The by product (8) that alkylamine on p-aminophenyl ethamine (6) and aromatic amine all react with sulphonate (5).

The present invention is investigated the temperature of reaction of above-mentioned ring-closure reaction, reaction times, the consumption of p-aminophenyl ethamine (6) and the consumption of alkali by conditional filtering experiment, avoids the generation of by products. Found by conditional filtering experiment: the temperature of reaction of above-mentioned ring-closure reaction should between 120-140 °C, when temperature of reaction is 100 °C, not exclusively, the productive rate of target compound (4) is lower in reaction, (exceeds 140 °C) and causes the increase in by product (8) when temperature of reaction is higher; The consumption of p-aminophenyl ethamine (6) should between 3-5 times of sulphonate (5) consumption, and the consumption of p-aminophenyl ethamine (6) obviously declines lower than the reaction yield of target compound during 3eq (4), and the consumption of p-aminophenyl ethamine (6) cannot significantly improve productive rate more than 5eq.

Alkali is tertiary amine, pyridine, DMAP, 1,8-diazabicylo-11-carbon-7-alkene, sodium carbonate, sodium bicarbonate, salt of wormwood or saleratus.

Solvent is ether, propyl ether, isopropyl ether, butyl ether, isoamyl oxide, hexyl ether, ethyl vinyl ether, butyl vinyl ether, methyl-phenoxide, phenyl ethyl ether, butyl phenylate, amyl group phenyl ether, ethyl benzyl ether, dibenzyl ether, diox, trioxane, tetrahydrofuran (THF), glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dibutyl ether, N, dinethylformamide, N, N-diethylformamide, dimethyl sulfoxide (DMSO), acetonitrile, methyl-formiate, ethyl formate, propyl formate, butyl formate, tetryl formate, pentyl formate, methyl acetate, ethyl acetate, propyl acetate, butylacetate, isobutyl acetate, pentyl acetate, methyl propionate, ethyl propionate, propyl propionate, butyl propionate, isobutyl propionate, amyl propionate, methylene dichloride, chloroform, tetracol phenixin, monochloroethane or 1,2-ethylene dichloride.​

Equipment and glassware:​

• 150 mL and 100 mL Pear shaped flask;
• 500 mL Closed steel reactor [you can use bottle from champagne with thick glass walls];
• Magnetic stirrer with heater;
• ~10 L Nitrogen (N2) or argonn (Ar) balloon (1 atm);
• Retort stand and clamp for securing apparatus;
• Flash chromatography kit;
• Rotovap machine;
• Buchner flask and funnel [Schott filter may be used for small quantities];
• Reflux condenser;
• Glass rod and spatula;
• Vacuum source;
• 100 mL x3; 50 mL x2 Beakers;
• Dewar bath;
• Solid CO2 (Dry Ice);
• Send bath;
• 250 mL x2 Erlenmeyer flasks;
• Glass rod and spatula;
• Laboratory grade thermometer (-50 °C to 200 °C) with flask adapter;
• 500 mL Separatory funnel;
• 100 mL Drip funnel.

Reagents:​

• Diisopropylamine 3.30 mL, 24 mmol (2);
• Tetrahydrofuran (THF) 120 mL anhydrous;
• n-Butyl Lithium 10 mL 2.4 mol/L, 24mmol;
• Benzyl cyanide 1.17 g, 10 mmol (1);
• Ethanal 1.06 g, 24 mmol (3);
• Methylsulfonyl chloride 2.74 g, 24 mmol (4);
• Distilled water, 121 mL;
• Ethylene dichloride (CH2Cl2) 400 mL;
• Sodium chloride aq solution (NaCl) ~200 mL;
• Sodium sulfate (Na2SO4) or Magnesium sulfate (MgSO4);
• Tetrahydrofuran (THF) 100 mL;
• Triethylamine (Et3N) 17.6 mL, 145 mmol;
• p-Aminophenyl ethamine (6) 12.0 g, 88.2 mmol;
• Ethanol (EtOH) 10 mL;
• Sulfuric acid 3 mL (H2SO4) conc.,
• Potassium carbonate (K2CO3) aqueous solution;
• Ethyl acetate (AcOEt) 50 mL.

​

1-(p-Aminophenethyl)-4-phenylpiperidine-4-carboxylic acid ethyl ester:
Boiling Point: 491.5±45.0 at 760 mm Hg;
Melting Point: 83 °C;
Molecular Weight: 352.47 g/mole;
Density: 1.1±0.1 g/mL;
CAS Number: 144-14-9.

Procedure ​

Methylsulfonic acid-3-cyano group-3-phenyl penta diester (5)

Diisopropylamine (3.30 mL, 24 mmol) (2) was dissolved in 20 mL anhydrous tetrahydrofuran (THF) in 150 ml pear shaped flask, cooled under inert atmosphere (Ar or N2) at -30 °C, 2.4 mol/L n-Butyl Lithium (10 mL, 24 mmol) was added dropwise, reacts 0.5 h; Add benzyl cyanide (1.17 g, 10 mmol) (1), continue stirring reaction 0.5 h; Ethanal (1.06 g, 24 mmol) (3) was added dropwise, reaction time is 0.5 h; Methylsulfonyl chloride (2.74 g, 24 mmol) (4) was added dropwise, continues stirring reaction 0.5 h; Slowly rise to 0 °C of reaction for 1 h, add 1 mL water termination reaction; To a tetrahydrofuran (THF) 50 mL methylene dichloride and 20 mL water was added and extract, aqueous phase was extracted again by 50 mL methylene dichloride; Merge organic phases, wash by brine, dry by anhydrous sodium sulfate, filter and white solid separate was obtained, yield 65% after concentrated through silica gel column chromatography.​

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Intermediate piperidine (7) and by product piperidines (8)
Sulphonate (5) (10.6 g, 29.4 mmol) is dissolved in 100 mL THF, adds Et3N (17.6 mL, 145 mmol) and p-aminophenyl ethamine (6) (12.0 g, 88.2 mmol), be warming up to 120 °C of reaction 20 h in closed reactor; Stopped reaction, is cooled to room temperature, solvent was evaporated, adds 200 mL methylene dichloride (CH2Cl2) and 100 mL water, mixture was extracted, aqueous phase was extracted again by 100 mL methylene dichloride; Merge organic phases, wash by brine, dry by anhydrous sodium sulfate, filter and separate to obtain piperidine (7) 38.20 g, yield 91.5% after concentrated through silica gel column chromatography; Another by product (8) 80.42 g.​

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1-(p-Aminophenethyl)-4-phenylpiperidine-4-carboxylic acid ethyl ester (Anileridine) (9)
Piperidines (7) (1.98 g, 6.5 mmol) is dissolved in 10 mL ethanol, is cooled to 0 °C, 3 mL H2SO4 conc. was added dropwise, stirring reaction 0.5 h in 100 ml pear shaped flask; warm reaction with reflux condenser, reaction 10 h; Be down to room temperature, reaction solution poured into cold K2CO3 aqueous solution, up to pH 10, extract by 100 mL ethyl acetate and 50 mL one more time; Merge organic phases, wash by brine, dry by anhydrous sodium sulfate, filters and separate to obtain anileridine 41.85 g (9), yield 80.6% after concentrated through silica gel column chromatography.​

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[1thejew1]

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